Process for preparing intermediates

ABSTRACT

The present invention is directed to a process for preparing intermediates that are useful to prepare certain antibacterial N-formyl hydroxylamine compounds which are peptide deformylase inhibitors. The process makes use a β-lactarn intermediate. Certain optically pure intermediates are also claimed.

This invention is directed to a process for preparing intermediates thatare useful to prepare certain antibacterial N-formyl hydroxylaminecompounds.

Peptide deformylase is a metallopeptidase found in prokaryotic organismssuch as bacteria. Protein synthesis in prokaryotic organisms begins withN-formyl methionine (fMet). After initiation of protein synthesis, theformyl group is removed by the enzyme peptide deformylase (PDF); thisactivity is essential for maturation of proteins. It has been shown thatPDF is required for bacterial growth (see Chang et al., J. Bacteriol.,Vol. 171, pp. 4071-4072 (1989); Meinnel et al., J. Bacteriol, Vol. 176,No. 23, pp. 7387-7390 (1994); Mazel et al., EMBO J., Vol. 13, No. 4, pp.914-923 (1994)). Since protein synthesis in eukaryotic organisms doesnot depend on fMet for initiation, agents that will inhibit PDF areattractive candidates for development of new anti-microbial andanti-bacterial drugs.

Co-pending application Ser. No. 10/171,706, filed Jun. 14, 2002(incorporated herein by reference in its entirety) and WO02/102790,disclose novel N-formyl hydroxylamine compounds that inhibit PDF and aretherefore useful as antibacterial agents. The compounds disclosedtherein are certainN-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl]-(carbonylamino-aryl or-heteroaryl)-azacyclo₄₋₇alkanes or thiazacyclo₄₋₇alkanes which aredescribed in more detail hereinafter. An improved process has beendiscovered for preparing intermediates useful for preparing theseN-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl]-(carbonylamino-aryl or-heteroaryl)-azacyclo₄₋₇alkanes or thiazacyclo₄₋₇alkanes which makes useof a particular β-lactam intermediate.

The present invention is directed to a novel process for preparingcertain intermediates which are useful to prepare certain N-formylhydroxylamine compounds which are useful for inhibiting bacteria.

More specifically, the present invention is directed to a process forpreparing a compound of the formula (VIII)

comprising Step A:

-   -   contacting a compound of the formula (I)    -   with a compound of the formula (II)        Y—O—NH₂  (II)    -   in the presence of a carboxy-activating agent, in a suitable        solvent under conditions suitable to form a compound of the        formula (III)        followed by Step B:    -   contacting compound (III) with a compound of the formula (XIII)        R′—SO₂—X′  (XIII)        in the presence of a base in a suitable solvent, under        conditions suitable to form a compound of the formula (IV)        followed by Step C:    -   contacting compound (IV) with a base in a suitable solvent under        conditions suitable to form a compound of the formula (V)        followed by Step D:    -   contacting compound (V) with a compound of the formula (VI)    -   in a suitable solvent optionally in the presence of an activator        under conditions suitable to form a compound of the formula        (VII)        followed by Step E:    -   contacting compound (VII) with a formylating agent in a suitable        solvent under conditions suitable to form compound (VIII);        wherein    -   Y is a hydroxy protecting group;    -   each of R₂, R₃, R₄ and R₅ is independently hydrogen or an        aliphatic group, or (R₂ and R₃) and/or (R₄ and R₅) collectively        form a C₄₋₇cycloalkyl;    -   X is —CH₂—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF₂—,        —C═N(OR)— or —CH(F)—;        -   wherein        -   R is alkyl;    -   G is —OH or O^(⊖)M^(⊕), wherein M is a metal or an ammonium        moiety;    -   R₁ is aryl or heteroaryl;    -   X′ is halo;    -   R′ is alkyl or aryl; and    -   n is 0 to 3, provided that when n is 0, X is —CH₂—.

When the desired product is an N-oxide of an aromatic moiety having anitrogen heteroatom, e.g., when R₁ is formula (X), (XIa) or (Xb),typically a pyridine derivative, it is necessary to perform anadditional step after Step E, i.e., to oxidize the N of the aromaticring (Step F). Therefore, the present invention includes Step F whichcomprises contacting the compound of formula (VIII), wherein R₁ isheteroaryl having an N heteroatom, with an oxidizing agent to form thecorresponding N-oxide derivative.

In addition to the above process comprising Steps A through E or F, thepresent invention is directed to each of the steps individually, and toany two or more sequential steps.

DETAILED DESCRIPTION OF THE INVENTION

In particular, the present invention provides a process for preparingintermediates useful in the preparation of aN-[1-oxo-2-alkyl-3-(N-hydroxyformamido)-propyl](carbonylamino-aryl or-heteroaryl)-azacyclo₄₋₇alkane or thiazacyclo₀₋₇alkane, e.g., a compoundof formula (IX)

wherein R₁, R₂, R₃, R₄, R₅, X and n are as defined above.

To convert the compound of formula (VIII) to the compound of formula(IX), the t hydroxy protecting group is removed using conventionalhydrogenolysis techniques known in the art, e.g., by contacting thecompound of formula (VIII) with a palladium catalyst, such as Pd/BaSO₄.

The R₁ moiety can be a heteroaryl, e.g., an azacyclo₄₋₇alkane, athiazacyclo₄₋₇alkane or an imidazacyclo₄₋₇alkane. Specific examples ofR₁ moieties in the compounds disclosed herein are heteroaryls of formula(X);

wherein each of R₆, R₇, R₈ and R₉, independently, is hydrogen, alkyl,substituted alkyl, hydroxy, alkoxy, acyl, acyloxy, SCN, halogen, cyano,nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl or formyl.

A more specific R₁ moiety is a heteroaryl of formula (XIa)

wherein R₆, R₇, R₈ and R₉ are as defined above for formula (X), e.g.,

-   -   wherein        -   a)            -   R₆ is nitro, alkyl, substituted alkyl, phenyl, hydroxy,                formyl, heteroalkylaryl, alkoxy, acyl or acyloxy;                preferably alkyl, especially C₁₋₇alkyl; hydroxyl; or                alkoxy, especially a C₁₋₇alkoxy; and            -   R₇, R₈ and R₉ are hydrogen; or        -   b)            -   R₆, R₈ and R₉ are hydrogen; and            -   R₇ is alkyl, substituted alkyl, phenyl, halogen, alkoxy                or cyano, preferably alkyl, especially C₁₋₇alkyl;                substituted alkyl, especially substituted C₁₋₇alkyl,                such as —CF₃; or alkoxy, especially C₁₋₇alkoxy; or        -   c)            -   R₆, R₇ and R₉ are hydrogen; and            -   R₈ is alkyl, substituted alkyl, halogen, nitro, cyano,                thioalkoxy, acyloxy, phenyl, alkylsulfonyl or                carboxyalkyl, preferably alkyl, especially C₁₋₇alkyl;                substituted alkyl, especially —CF₃; halogen such as                chloro, bromo or fluoro; or carboxyalkyl; or        -   d)            -   R₆, R₇ and R₈ are hydrogen; and            -   R₉ is alkyl, halogen or hydroxy; or        -   e)            -   R₇ and R₉ are hydrogen; and            -   each of R₆ and R₈, independently, is halogen, alkyl,                substituted alkyl, phenyl or cyano; or        -   f)            -   Each of R₇ and R₉ is alkyl or substituted alkyl; and            -   R₆ and R₈ are hydrogen; or        -   g)            -   R₆ and R₉ are hydrogen;            -   R₇ is alkyl or substituted alkyl; and            -   R₈ is nitro; or        -   h)            -   R₈ and R₉ are hydrogen;            -   R₆ is cyano; and            -   R₇ is alkoxy; or        -   i)            -   R₇ and R₈ are hydrogen; and            -   R₆ is alkyl, substituted alkyl, alkoxy or SCN; and            -   R₉ is alkyl or substituted alkyl; or        -   j)            -   R₆ and R₇ are hydrogen;            -   R₈ is nitro or halogen; and            -   R₉ is alkyl or substituted alkyl; or        -   k) R₆, R₇, R₈ and R₉ are hydrogen; or,        -   l)            -   R₆ and R₇ together with the carbon atoms to which they                are attached form a phenyl group, preferably substituted                with hydroxy; and            -   R₈ and R₉ are hydrogen; or        -   m)            -   R₆ and R₇ are hydrogen; and            -   R₈ and R₉ together with the carbon atoms to which they                are attached form a phenyl group; or        -   n) n is 0; or        -   o)            -   n is 0;            -   each of R₆, R₇, R₈ and R₉, independently, is hydrogen,                alkyl or halogen; and            -   more particularly, R₆, R₇, R₈ and R₉ are hydrogen; or        -   p)            -   n is 0;            -   R₆, R₈ and R₉ are hydrogen; and            -   R₇ is alkyl; or        -   q)            -   n is 0;            -   R₆, R₇ and R₉ are hydrogen; and            -   R₈ is alkyl or halogen.

In another embodiment, R₁ is of formula (Xb)

wherein

-   -   R₆, R₇, R₈ and R₉ are as defined above for formula (X); in        particular, R₇ and R₈ together with the carbon atoms to which        they are attached form a phenyl group; and    -   R₆ and R₉ are hydrogen.

In yet another embodiment, the R₁ is of formula (XI)

wherein each of R₆, R₇, R₈ and R₉ independently is hydrogen, alkyl,substituted alkyl, phenyl, halogen, hydroxy or alkoxy, e.g.,

-   -   wherein        -   a)            -   R₆ and R₈ are hydrogen;            -   R₉ is hydrogen or alkyl; and            -   R₇ is alkyl, substituted alkyl or phenyl; or        -   b)            -   R₆, R₇ and R₉ are hydrogen; and            -   R₈ is halogen, alkyl or substituted alkyl; or        -   c)            -   R₇, R₈ and R₉ are hydrogen; and            -   R₆ is hydroxy.

In a particularly useful embodiment the heteroaryl is of the formula(XIa)

wherein R₆, R₇, R₈ and R₉ are as defined above for formula (XI), inparticular where R₈, R₇, and R₉ are hydrogen and R₈ is fluoro.

In another embodiment, R₁ is an unsubstituted phenyl or the phenyl issubstituted with alkoxy, e.g., methoxy; or aryloxy, e.g., phenoxy.

In another embodiment, the R₁ is of formula (XII)

wherein each of R₁₀ and R₁₁, independently, is hydrogen or halogen. Inparticular, R₁₀ and R₁₁ are both either hydrogen or both halogen.

In the compound of formula (I), M is a metal, typically a mono- ordi-valent metal or an ammonium moiety. Typical metals include Mg, Ca,Na, K Li and the like. The ammonium moiety is of the formula

wherein R″ is hydrogen, alkyl, substituted alkyl, aryl or substitutedaryl.

The ammonium moiety can be racemic or chiral. An example of an ammoniummoiety is R-α-methylbenzylammonium. Examples of R″ groups includehydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl, methylbenzyl andthe like.

Unless otherwise stated, the following terms as used in thespecification have the following meaning.

The term “cycloalkane” or “cycloalkyl” contains from 3- to 7-ring carbonatoms, and is, e.g., cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

The term “azacyclo₄₋₇alkane” contains 1-ring heteroatom which is anitrogen. It contains from 4-7, and especially 4- or 5-ring atomsincluding the heteroatom.

The term “thiazacyclo₄₋₇alkane” contains 2-ring heteroatoms, nitrogenand sulfur. It contains from 4-7, and especially 5-ring atoms includingthe heteroatoms.

The term “imidazacyclo₄₋₇alkane” contains 2-ring heteroatoms which areboth nitrogen. It contains from 4-7, and especially 5-ring atomsincluding the heteroatoms.

The term “aliphatic group” refers to saturated or unsaturated aliphaticgroups, such as alkyl, alkenyl or alkynyl, cycloalkyl or substitutedalkyl including straight-chain, branched-chain and cyclic groups havingfrom 1-10 carbons atoms. Preferably “alkyl” or “alk”, whenever itoccurs, is a saturated aliphatic group or cycloalkyl, more preferablyC₁₋₇alkyl, particularly C₁₋₄alkyl. Examples of “alkyl” or “alk” include,but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl,cyclopropyl and especially n-butyl.

The term “substituted alkyl” refers to an alkyl group that issubstituted with one or more substituents preferably 1-3 substituentsincluding but not limited to, substituents, such as halogen, loweralkoxy, hydroxy, mercapto, carboxy, cycloalkyl, aryl, heteroaryl and thelike. Examples of substituted alkyl groups include, but are not limitedto, —CF₃, —CF₂—CF₃, hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl,1- or 2-ethoxyethyl, carboxymethyl, 1- or 2-carboxyethyl and the like.

The term “aryl” or “Ar” refers to an aromatic carbocyclic group of 6-14carbon atoms having a single ring including, but not limited to, groups,such as phenyl; or multiple condensed rings including, but not limitedto, groups, such as naphthyl or anthryl; and is especially phenyl.

The term “heteroaryl” or “HetAr” refers to a 4- to 7-membered,monocyclic aromatic heterocycle or a bicycle that is composed of a 4- to7-membered, monocyclic aromatic heterocycle and a fused-on benzene ring.The heteroaryl has at least one hetero atom, preferably one or twoheteroatoms including, but not limited to, heteroatoms, such as N, O andS, within the ring. A preferred heteroaryl group is pyridinyl,pyrimidinyl or benzdioxolanyl.

The aryl or heteroaryl may be unsubstituted or substituted by one ormore substituents including, but not limited to, C₁₋₇alkyl, particularlyC₁₋₄alkyl, such as methyl, hydroxy, alkoxy, acyl, acyloxy, SCN, halogen,cyano, nitro, thioalkoxy, phenyl, heteroalkylaryl, alkylsulfonyl andformyl.

The term “carbonylamine”, as used herein, refers to a —NHC(O)— groupwherein the amino portion of the group is linked to the aryl/heteroaryland the carbonyl portion of the group is linked to theazacyclo₄₋₇alkane, thiazacyclo₄₋₇alkane or imidazacyclo₄₋₇alkane.

The term “heteroalkyl” refers to saturated or unsaturated C₁₋₁₀alkyl asdefined above, and especially C₁₋₄heteroalkyl which contain one or moreheteroatoms, as part of the main, branched or cyclic chains in thegroup. Heteroatoms may independently be selected from the groupconsisting of —NR—, where R is hydrogen or alkyl, —S—, —O— and —P—;preferably —NR—, where R is hydrogen or alkyl; and/or —O—. Heteroalkylgroups may be attached to the remainder of the molecule either at aheteroatom (if a valence is available) or at a carbon atom. Examples ofheteroalkyl groups include, but are not limited to, groups, such as—O—CH₃, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃, —S—CH₂—CH₂—CH₃, —CH₂—CH(CH₃)—S—CH₃and —CH₂—CH₂—NH—CH₂—CH₂—.

The heteroalkyl group may be unsubstituted or substituted with one ormore substituents, preferably 1-3 substituents including, but notlimited to, alkyl, halogen, alkoxy, hydroxyl, mercapto, carboxy andespecially phenyl. The heteroatom(s) as well as the carbon atoms of thegroup may be substituted. The heteroatom(s) may also be in oxidizedform.

The term “alkoxy”, as used herein, refers to a C₁₋₁₀alkyl linked to anoxygen atom, or preferably C₁₋₇alkoxy, more preferably C₁₋₄alkoxy.Examples of alkoxy groups include, but are not limited to, groups suchas methoxy, ethoxy, h-butoxy, tert-butoxy and allyloxy.

The term “acyl”, as used herein, refers to the group —(O)CR, where R isalkyl, especially C₁₋₇alkyl, such as methyl. Examples of acyl groupsinclude, but are not limited to, acetyl, propanoyl and butanoyl.

The term “acyloxy”, as used herein, refers to the group —OC(O)R, whereinR is hydrogen, alkyl, especially C₁₋₇alkyl, such as methyl or ethyl, orphenyl or substituted alkyl as defined above.

The term “alkoxycarbonyl”, as used herein, refers to the group —COOR,wherein R is alkyl, especially C₁₋₇alkyl, such as methyl or ethyl.

The term “halogen” or “halo”, as used herein, refers to chlorine,bromine, fluorine, iodine and is especially fluorine.

The term “thioalkoxy”, as used herein, means a group —SR, where R is analkyl as defined above, e.g., methylthio, ethylthio, propylthio,butylthio and the like.

The term “heteroalkylaryl”, as used herein, means a heteroalkyl group,e.g., —O—CH₂— substituted with an aryl group, especially phenyl. Thephenyl group itself may also be substituted with one or moresubstituents, such as halogen, especially fluoro and chloro; and alkoxysuch as methoxy.

The term “alkylsulfony”, as used herein, means a group —SO₂R, wherein Ris alkyl especially C₁₋₇alkyl, such as methyl sulfonyl.

“Protecting group” refers to a chemical group that exhibits thefollowing characteristics: 1) reacts selectively with the desiredfunctionality in good yield to give a protected substrate that is stableto the projected reactions for which protection is desired, 2) isselectively removable from the protected substrate to yield the desiredfunctionality; and 3) is removable in good yield by reagents compatiblewith the other functional group(s) present or generated in suchprojected reactions. Examples of suitable protecting groups may be foundin Greene et al., “Protective Groups in Organic Synthesis”, 3^(rd) Ed.,John Wiley & Sons Inc., NY (1999). Preferred hydroxy protecting groupsinclude benzyl, Fmoc, TBDMS, photolabile protecting groups, such asNvom, Mom and Mem. Other preferred protecting groups include NPEOC andNPEOM.

It will be appreciated that the compounds disclosed herein may exist inthe form of optical isomers, racemates or diastereoisomers. Inparticular, in the compounds disclosed herein where R₄ and R₅ aredifferent, the carbon atom to which the R₄ and R₅ groups are bonded is achiral center and such compounds can exist in the R, S or racemic forms.It is preferred that the process of the invention prepares the Roptically pure form. By “optically pure” is meant that the enantiomericpurity is greater than 50%, preferably greater than 80%, more preferablygreater than 90%, and most preferably greater than 95%. The opticallypure R isomer of compound (I) can be used, in which case all subsequentcompounds in the synthesis will remain in the R optically pure form,with respect to the same chiral carbon atom. If an optically purecompound is used as the starting material, purification from theundesired diastereomer can be avoided at later steps. Such R form ofcompound (I) is represented below:

wherein R₂, R₃, R₄ and R₅ are as defined above. The optically pure formof compound (I) is novel provided that when either R₄ or R₅ is hydrogen,the other substituent, i.e., R₄ or R₅ is not hydrogen or methyl. In aparticular embodiment of the novel compound of formula (I), R₅ ishydrogen and R₄ is C₂₋₁₀alkyl, in a more particular embodimentC₂₋₇alkyl, and in a even more particular embodiment C₄alkyl.

In a further embodiment an optically pure compound of formula (I) t R₂,R₃, and R₅ are hydrogen and R₄ is alkyl; such a compound has thestructure (Ia):

Another embodiment in compound (I) is where R₄ is n-butyl, where suchcompound has the structure (Ib)

Another embodiment is where R₂, R₃ and R₅ are hydrogen and R₄ isn-butyl; such compound has the structure (Ic):

More particular examples of the optically pure compound of formula (I)are as follows:

Alternatively, the racemate form of compound (I) can be used and thenthe R form can be resolved at a later step and the R form used forsubsequent steps. For example, the compound formed after opening theβ-lactam ring, i.e., compound (VII), the product of Step D, can beresolved into its RS and SS diastereomers and only the RS diastereomerused for subsequent steps. The RS diastereomer of compound (VII) isdepicted below:

-   -   wherein R₂, R₃, R₄ R₅ Y, X, R₁ and n are as defined above,        provided that R₄ and R₅ are different.

The diastereoisomers are resolved using standard techniques known in theart, for example, using silica gel column chromatography and an ethylacetate/hexane solvent system (see, e.g., the methods taught in Chapter4 of “Advanced Organic Chemistry”, 5^(th) edition, J. March, John Wileyand Sons, NY (2001)).

In the compounds disclosed herein, the following significances arespecific embodiments individually or in any sub-combination:

-   1. R₁ is a heteroaryl of formula (IIa), wherein R₆, R₇ and R₉ are    hydrogen and R₈ is methyl or trifluoromethyl; or R₆, R₇ and R₈ are    hydrogen and R₉ is fluoro; or R₆, R₈ and R₉ are hydrogen and R₇ is    ethyl or methoxy; or R₇, R₈ and R₉ are hydrogen and R₆ is hydroxy;    or R₇ and R₈ are hydrogen, R₆ is methoxy and R₉ is methyl; or R₁ is    a heteroaryl of formula (IIIa), wherein R₆, R₇ and R₉ are hydrogen    and R₈ is fluoro or trifluoromethyl; or R₆, R₈ and R₉ are hydrogen    and R₇ is ethyl; preferably R₁ is a heteroaryl of formula (IIa),    wherein R₆, R₈ and R₉ are hydrogen and R₇ is ethyl or a heteroaryl    of formula (IIIa), wherein R₆, R₇ and R₉ are hydrogen and R₈ is    fluoro.-   2. X is —CH₂—, —CH(OH)—, —CH(OR)—, —CF₂— or —CH(F)—, preferably X is    —CH₂—;-   3. R₄ is alkyl, preferably C₁₋₇alkyl, such as n-butyl;-   4. n is 1.

Temperature and pressure are not known to be critical for carrying outany of the steps of the invention, i.e., Steps A through E. Generally,for any of the steps, a temperature of about −10° C. to about 150° C.,preferably about 0° C. to about 80° C., is typically employed. Typicallyabout atmospheric pressure is used for convenience; however, variationsto atmospheric pressure are not known to be detrimental. Oxygen is notknown to be detrimental to the process, therefore for convenience thevarious steps can be performed under ambient air, although an inertatmosphere, such as nitrogen or argon, can be used if desired. Forconvenience equimolar amounts of reactants are typically used; howevermolar ratios can vary from about 1 to 2 equivalents, relative to theother reactant. The pH for the various steps is typically about 2 toabout 12. The solvent used for the various steps are typically organicsolvents, although in some situations aqueous/organic solvents can beused. Examples of suitable solvents include dioxane; mtehylene chloride;dichloromethane; toluene, acetone; methyl ethyl ketone; THF; isopropylacetate; DMF; alcohols, especially higher branched alcohols, such ast-butanol; and the like.

For Step A, a typical temperature is about 0° C. to about 50° C.,preferably about 5° C. to about 35° C.; and a typical reaction time isabout 1 hour to about 10 hours, preferably about 2 hours to about 5hours. A pH of about 2 to about 7, preferably about 3 to about 5, morepreferably about 4, is typically employed. The carboxy-activating agentcan be for example, DCC, CDMT, EDCl and the like. The amount ofcarboxy-activating agent employed is typically about 0.5 to about 2molar equivalents relative to compound (I). The solvent is water or amixture of water and one or more organic solvents, such as THF, dioxane,alcohols, such as methanol, ethanol and the like. Specific examples ofsolvents include THF/water and water. In the event that an ammonium saltof compound (I) is used in the process, the salt will be dissolved inwater containing at least a molar equivalent amount of base, such asalkaline metal hydroxide, such as NaOH and KOH; the base is added toliberate the free amine which is extracted into the organic phase, theaqueous phase is used for the coupling reaction.

For Step B, a typical temperature is about −20° C. to about 25° C., moretypically about −5° C. to about 5° C.; and a typical reaction time isabout 1 hour to about 2 hours, more typically about 2 hours to about 5hours. For Step B, an alcoholic solvent should not be used. For reactant(XIII), X′ is preferably chloro and R′ is preferably lower alkyl orphenyl, with CH₃SO₂Cl and tosyl chloride being most typical. The pH forStep B is basic and is typically about 9 to about 10. The base used forStep B can be any conventional base known in the art that will activatethe hydroxy group of compound (III), and such base will be used in ahydroxyl-activating amount which is at least about 1 molar equivalentrelative to compound (III). The base can also act as solvent in whichcase it will be present in a solvating amount which is in excess of theabove amount. Examples of bases that can be employed include pyridine;DMAP; a trialkylamine, e.g., trimethylamine; resin-bound bases; Hunigbases; and the like. A particular solvent is pyridine, THF or EtOAc.

For cyclization Step C, a typical temperature is about 20° C. to about150° C., more typically about 40° C. to about 80° C.; and a typicalreaction time is about 1 hour to about 20 hours, more typically about 2hours to about 4 hours. The pH for Step C is basic, typically, about 8to about 12. The base used in Step C can be any base known in the artthat is capable of de-protonating the amide group of compound (IV).Examples of suitable bases include inorganic or organic bases, such aspotassium carbonate; lithium carbonate; sodium carbonate; lithiumbicarbonate; sodium bicarbonate; alkyl lithium, e.g., butyl lithium; andthe like. The amount of base employed is a de-protonating amount whichis typically in molar excess to the amount of compound (IV), e.g., about1-5 equivalents relative to compound (IV). For certain solvents, such asTHF, dioxane, dimethoxyethane and the like, it may be necessary to use acatalytic amount of a phase transfer catalyst, such astrialkylarylammonium salt or a tetraalkylammonium salt, e.g.,tetrabutylammonium chloride or tetrabutylammonium bromide. The examplesof solvents are ketones, such as acetone or methylethylketone.

For Step D, a typical temperature is about 30° C. to about 150° C., moretypically about 60° C. to about 80° C.; and a typical reaction time isabout 3 hours to about 20 hours, more typically about 5 hours to about10 hours. The pH for Step D is typically about 5 to about 11. Theactivator for Step D is a compound which protonates the β-lactam ketooxygen; such activators include, e.g., mild (weak) organic acids, suchas branched or unbranched carboxylic acids, e.g., 2-ethylhexanoic acid,acetic acid, isobutryic acid and the like. If an aqueous alcoholicsolvent is used an activator is not needed; examples ofd aqueousalcoholic solvents include MeOH.H₂O, EtOH.H₂O and the like. If anactivator is used a typical solvent is THF, dioxane or dimethoxyethane.If an activator is used it is used in an protonating amount which istypically about 0.1 molar equivalents to about 2 molar equivalentsrelative to compound (V).

For Step E, a typical temperature is about −30° C. to about 50° C., moretypically about 0° C. to about 25° C.; and a typical reaction time isabout 10 minutes to about 5 hours, more typically about 20 minutes toabout 1 hour. The pH for Step E is not critical and can varyconsiderably. For Step E the solvent should not be an alcoholic solvent.The formylating agent can be, for example, HCO₂H/Ac₂O,trifluoroethylformate, and the like, and is present in a formylatingamount which is typically about 1 molar equivalent to about 2 molarequivalents relative to compound (VII). A typical solvent is EtOAc,isopropylacetate, t-butylacetate or THF.

For Step F, a typical temperature is about 10° C. to about 35° C., moretypically about 20° C. to about 22° C.; and a typical reaction time isabout 60 minutes to about 18 hours, more typically about 4 hours toabout 8 hours. The pH for Step F is typically about 4 to about 8. Thesolvent for Step F is typically an organic solvent, i.e., ethyl acetate,iso-propyl acetate, methylene chloride, and the like. The oxidizingagent can be a conventional agent known in the art, e.g., as disclosedin March, “Advanced Organic Chemistry”, Chapter 19, 5^(th) edition,Wiley Interscience, NY, incorporated herein by reference. Typicaloxidizing agents include urea/hydrogen peroxide with phthalic anhydride;magnesium monoperoxyphthalate (MMPP); MCPBA, Oxone (available fromAldrich), and the like.

Insofar as the production of starting materials is not particularlydescribed, the compounds are known or may be prepared analogously tomethods known in the art or as disclosed in the examples hereinafter.

The following abbreviations are used:

-   Ac=acetyl-   CDMT=chlorodimethoxy triazine-   DIEA=diisopropylethylamine-   DCC=dicyclohexylcarbodimide-   DMAP=dimethylaminopyridine-   DMF=dimethylformamide-   EDCl=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   2-EHA=2-ethylhexanoic acid-   EtOAc=ethyl acetate-   EtOH=ethanol-   Fmoc=9-fluorenylmethyl-oxycarbonyl-   HPLC=high performance liquid chromatography-   MeOH=methanol-   Mom=methoxy methyl ether-   Mem=methoxy ethoxy methyl ether-   NPEOC=4-nitrophenethyloxycarbonyl-   NPEOM=4-nitrophenethyloxy-methyloxycarbonyl-   Nvom=nitroveratryl oxymethyl ether-   TBDMS=t-butyidimethylsilyl,-   TMSCI=trimethylsilyl chloride-   RT=room temperature-   THF=tetrahydrofuran

The following examples illustrate the process of the invention butshould not be interpreted as a limitation thereon:

Product numbers in the following examples refer to reaction scheme Idepicted immediately above.

Product A3

A flask was charged with 2.80 g (19.2 mmol) of A1, 80 mL of THF, 20 mLof water, and 4.73 g (38.4 mmol) of A2. The resulting solution wasstirred at RT and the pH of the solution was adjusted to 4.2-4.5 with 2NHCl acid solution.

5.52 g (28.8 mmol) of EDCl was added in three portions (2.12 g, 2.26 g,1.14 g) within 15 minutes. The resulting solution was stirred at RT for2 hours, and the pH of the solution was adjusted to 4.2-4.5 during thereaction. The progress of the reaction was monitored by HPLC. After thereaction was completed, THF was evaporated under reduced pressure, andthe residue was extracted with 3×70 mL of ethyl acetate and the combinedorganic phase was washed sequentially with 2×50 mL of 10% citric acidsolution, 50 mL of water, 2×50 mL of 5% sodium bicarbonate solution and50 mL brine dried over MgSO₄. The evaporation of organic solventafforded 2.4 g of A3 (94% yield).

Product A4

A flask was charged with 7.53 g (30 mmol) of A3 and 30 mL of pyridine.The resulting solution was cooled to 0±2° C. with ice-salt bath. Then,2.78 mL (36 mmol) of methanesulfonyl chloride was slowly added andmaintained the temperature at 0±2° C. for 1.5 hours. After the reactionmonitored by HPLC was completed, the mixture was poured into cold 120 mLof 1N HCl acid, and extracted with 2×100 mL of ethyl acetate. Theorganic phase was washed sequentially with 2×70 mL of 1N HCl acid untilthe aqueous solution was acidic, 100 mL of saturated sodium bicarbonatesolution, 100 mL of brine and dried over MgSO₄. The evaporation oforganic solvent gave 9.87 g of A4 (˜100% yield).

Product A5

A flask was charged with 16.07 g (116 mmol) of potassium carbonate(powdered), 631 mL of acetone. The suspension was heated to reflux.Then, 12.49 g (38 mmol) of A4 in 91 mL of acetone was slowly added (30minutes). The resulting mixture was stirred at reflux for 1 hour. Afterthe reaction monitored by HPLC was completed, the suspension wasfiltered through celite, and washed with 200 mL of ethyl acetate. Theorganic solvent was concentrated and diluted with 400 mL of ethylacetate and washed with 100 mL of 1N HCl acid, 100 mL of saturatedsodium bicarbonate solution, 100 mL of brine and dried over MgSO₄. Theconcentration of organic solvent under reduced pressure afforded 7.96 gof A5 (liquid, 90% yield).

When the A5 is racemic, attacking with chiral A6 results in twodiastereomers A7 and A7′ They can be separated by silica gel columnusing EtOAc and hexanes (1:1) as eluent system. A7 was the secondfraction from column and it was identified by comparing with theauthentic sample from the other approach.

There are several methods to open the β-lactam ring in A5. The resultsfor opening the lactam ring are summarized in Table 1. TABLE 1 ReactionConditions and Results for Coupling A5 and A6 Temp. Time A5 A6 SolventyAdditives (° C.) (h) Remarks 5 mmol 6 mmol MeOH (25 ml) 22 1 None 65 1None  0.1 mL - 2 EHA  66 1 Non 1 mL - H2O 22 15 None 1 mL - H2O 70 2None MeOH (5 mL 2 mL - H2O 82 17 100% conversion 5 mmol 7.5 mmol Toluene115 3 None   0.5 mL - TMSCI 116 4 3% conversion    1 mL - 2EHA 115 3100% conversion one bypd. 5 mmol 6 mmol THF 0.2 mL - 2EHA  70 7 98%conversionProduct A7 and A7′

A flask was charged with 1.165 g (5 mmol) of A5, 10 mL of THF, 1.24 g (6mmol) of A6 and 0.2 mL (1.25 mmol) of 2-ethyl hexanoic acid. Theresulting solution was heated to reflux (70° C.) for 7 hours, and thereaction was monitored by HPLC. THF was evaporated and the residue wasdissolved in 100 mL of ethyl acetate. The organic layer was washedsequentially with 25 mL of water, 25 mL of saturated sodium bicarbonate,25 mL of brine and dried over MgSO₄. The concentration of organicsolvent gave oil which was further purified by column separation onsilica gel to give 0.95 g of A7 and 0.85 g of A7′ (84% total yield).

Product A8

A small flask was charged with 0.35 g (3.43 mmol) of acetic anhydride,and cooled to <10° C. Then, 0.50 g (10.8 mmol) of formic acid (96%) wasslowly added to the it (25 minutes). After the addition, the solutionwas warmed to RT and stirred at this temperature for 30 minutes.

A flask was charged with 0.62 g (1.40 mmol) of A7 and 5 mL of ethylacetate. The solution was cooled to −3 to 0° C. with ice-salt bath.Then, the solution prepared from above procedure was slowly added (30minutes). After addition, the reaction was completed (monitored byHPLC). The solution was diluted with 100 mL of ethyl acetate, and washedsequentially with 25 mL of water, 2×25 mL of saturated sodiumbicarbonate, 25 mL of brine and dried over MgSO₄. The organic solventwas evaporated to give 0.61 g of A8.

The lactam ring can also be opened by a base, such as lithium hydroxide.As depicted below, the opening ring product was obtained in 91.5% yieldwith high purity after work-up.

A flask was charged with 1.165 g (5 mmol) of A5, 15 mL of THF, 5 mL ofmethanol. The resulting solution was cooled to 0° C. Then, 0.25 g oflithium hydroxide monohydrate in 5 mL of water was added. The solutionwas stirred and allowed to warm to 22° C. for 18 hours. After thereaction monitored by HPLC was completed, the pH of the mixture wasadjusted to 2 with 2N HCl acid. The organic solvents were removed, andthe residue was extracted with 2×50 mL of ethyl acetate, and washed with2×30 mL of brine aid dried over MgSO₄. The evaporation the organicsolvent gave 1.15 g of desired product in 91.5% yield with high purity.

The product numbers in the following examples refer to Reaction Scheme 1depicted immediately above.

Compound C3

From (2R)-2-(hydroxymethyl)hexanoic acid:

A 5 L, 4-necked, round-bottomed flask, equipped with a mechanicalstirrer, digital thermometer and nitrogen inlet-outlet, is charged with102.39 g of (2R)-2-(hydroxymethyl)hexanoic acid, 123.0 g ofO-benzylhydroxylamine hydrochloride and 2.25 L of water. Adjust the pHby adding one equivalent of NaOH to a pH of 4-5. Stir the reactionmixture at 18° C.±3° C. (external temperature: 15-18° C.) for 30 minutesto give a cloudy solution. Add 161.3 g of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCl)over a period of 60 minutes in 6 portions, while maintaining theinternal temperature at 18° C.±3° C. (external temperature: 10° C.±3°C.). Wash the funnel once with 50 mL of water. Stir the thick suspensionat 20° C.±3° C. for 2 hours. Filter the solids through a polypropylenefilter cloth and a Büchner funnel then wash the flask and filter cakeonce with 0.5 L of water. Air-dry the cake at 20° C.±3° C. (housevacuum) for 2 hours, then dry the wet cake (˜265 g weight) at 65° C.±3°C. (15 mbar) for 24 hours to give 162 g of(2R)-2-(hydroxymethyl)-N-(phenylmethoxy)hexanamide (C3) as a white solidin 95% yield. m.p. 100-102° C.; [α]_(D) ²⁵=+0.556 (c, 1.0, MeOH).

From Sodium Salt:

A 5 L, 4-necked, round-bottomed flask, equipped with a mechanicalstirrer, digital thermometer and nitrogen inlet-outlet, is charged with117.8 g of (2R)-2-(hydroxymethyl)hexanoic acid sodium salt, 123.0 q ofO-benzylhydroxylamine hydrochloride, and 2.25 L of water.

Stir the reaction mixture at 18° C.±3° C. (external temperature: 15-18°C.) for 30 minutes to give a cloudy solution. Add 161.3 g of1-[3-(dimethylamino)propyl]-3-EDCl over a period of 60 minutes in 6portions, while maintaining the internal temperature at 18° C.±3° C.(external temperature: 10° C.±3° C.). Wash the funnel once with 50 mL ofwater. Stir the thick suspension at 20° C.±3° C. for 2 hours. Filter thesolids through a polypropylene filter cloth and a Büchner funnel thenwash the flask and filter cake once with 0.5 L of water. Air-dry thecake at 20° C.±3° C. (house vacuum) for 2 hours, then dry the wet cake(˜265 g weight) at 65° C.±3° C. (15 mbar) for 24 hours to give 162 g of(2R)-2-(hydroxymethyl)N-(phenylmethoxy)hexanamide (C3) as a white solidin 95% yield. m.p. 100-102° C.; [α]_(D) ²⁵=+0.556 (c, 1.0, MeOH).

From R-α-methylbenzylammonium Salt:

A 12 L, 4-necked, round-bottomed flask, equipped with a mechanicalstirrer, digital thermometer and nitrogen inlet-outlet, is charged with300 g of (2R)-2-(hydroxymethyl)hexanoic acid R-α-methylbenzylammoniumsalt and 1.12 L of water and 2.2 L of tert-butyl methyl ether. Cool thesuspension to an internal temperature at 18-22° C. over a period of 20minutes and add a solution of 94.24 g aqueous NaOH (50% w/w). Stir thesolution for 30 minutes and separate layers. Wash the aqueous layer with2.2 L of tert-butyl Methyl ether. Separate layers and save the aqueouslayer containing the (2R)-2-(hydroxymethyl)hexanoic acid sodium salt andproceed as mentioned in Example 1 to get compound 3 in 91% yield; m.p.100-102° C.; [α]_(D) ²⁵=+0.556 (c, 1.0, MeOH).

Alternatively the corresponding potassium, lithium or calcium salts of(2R)-2-(hydroxymethyl)hexanoic acid were also used in this step asdescribed in Example 2.

In addition, any other ammonium salts of (2R)-2-(hydroxymethyl)hexanoicacid can be used after removing the amine component as described inExample 3.Compounds C3→C4

A flask was charged with 7.53 g (30 mmol) of C3, and 15 mL of pyridine.The resulting solution was cooled to 0±4° C. with ice-salt bath. Then,2.78 mL (42 mmol) of methanesulfonyl chloride was slowly added andmaintained temperature at 0±4° C. for 2 hours. After the reactionmonitored by HPLC was completed, the mixture was quenched by slowaddition of 95 mL of 2N HCl at −5±5° C., then warmed to RT and stirredat this temperature for 2 hours. The solids were filtered and washedwith water (30 mL), dried in an oven at 50° C. for 14 hours to give 9.86g of C4 (˜100% yield); [α]_(D) ²⁵=+5.901 (c, 1.0, MeOH).Compound C5

A flask was charged with 3.86 (27.8 mmol) of potassium carbonate, 50 mLof THF and 0.3 g of tetrabutylammonium bromide. The suspension washeated to 40° C. and stirred at this temperature for 30 minutes. Then,3.0 g (9.1 mmol) of C4 was added in one portion. The mixture was heatedto 60° C. and stirred at this temperature for 1 hour. After thereaction, The organic solvent was concentrated to 8.58 mL/g (THF/C5) forthe following step without further purification. The pure C5: [α]_(D)²⁵=+24.63 (c, 1.0, MeOH).

Compound C6

A flask was charged with 2.12 g (9.1 mmol) of C5 from previousexperiment in 20 mL of THF, 2.26 g (10.9 mmol) of Y5a and 0.8 mL of2-ethyl hexanoic acid. The resulting solution was heated to reflux (70°C.) for 8 hours, and the reaction was monitored by HPLC. THF wasevaporated and the residue was dissolved in 50 mL of ethyl acetate.

The organic layer was washed sequentially with 20 mL of water 2×20 mL of1 N HCl solution, 20 mL of saturated sodium bicarbonate and 20 mL ofbrine. The concentration of organic solvent gave 3.78 g of C6 (94%yield) in 21 mL of ethyl acetate which was used for the following step.The pure C6: [α]_(D) ²⁵=−74.43 (c, 1.0, MeOH).Step C6+C7→C8

A flask was charged with 22.6 g (0.22 mole) of acetic anhydride, andcooled to <10° C. Then, 32.3 g (0.674 mole) of formic acid (96%) wasslowly added to the flask (25 minutes), and maintained the temperaturebetween 5-10° C. After addition, the solution was warmed to RT andstirred at this temperature for 30 minutes.

A flask was charged with 36 g (81.4 mmol) of C6 and 200 mL of ethylacetate. The solution was cooled to −5° C. to −10° C. with methanol-icebath. Then, the solution prepared from above procedure was slowly added(30 minutes). After the reaction was completed (monitored by HPLC). Thesolution was diluted with 100 mL of water and warmed to 10° C., andstirred for 20 minutes. The organic layer was washed sequentially with3×100 mL of saturated sodium bicarbonate, 100 mL of brine. Added 374 mLof ethyl acetate, and distilled ethyl acetate under vacuum in housevacuum until the residue volume about 274 mL. Heated the solution >50°C., and added 822 mL of heptane while maintaining the temperature <50°C. Cooled the solution to 10° C., and seeded with Plant A11. Maintainedthe temperature of the suspension at 0-5° C. for 4 hours, then warmed toRT (24° C.) for 14 hours, cooled to −5° C. to −10° C. for 3 hours. Thesolid was filtered and washed with 100 mL of cold heptane/ethyl acetate(4/1 by volume) and dried to give 24.0 g of C8 in 63% yield. The pureC8: [α]_(D) ²⁵=−97.02 (c, 1.0, MeOH).

1. A process for preparing a compound of the formula (VIII)

comprising step A: contacting a compound of the formula (I)

with a compound of the formula (II) Y—O—NH₂ (II) in the presence of acarboxy activating agent, in a suitable solvent under conditionssuitable to form a compound of the formula (III)

followed by step B: contacting compound (III) with a compound of theformula (XIII)R′—SO₂—X′ in the presence of a base in a suitable solvent, underconditions suitable to form a compound of the formula (IV)

followed by Step C: contacting compound (IV) with a base in a suitablesolvent under conditions suitable to form a compound of the formula (V)

followed by Step D: contacting compound (V) with a compound of theformula (VI)

in a suitable solvent optionally in the presence of an activator underconditions suitable to form a compound of the formula (VII)

followed by Step E: contacting compound (VII) with a formylating agentin a suitable solvent under conditions suitable to form compound (VIII);wherein Y is a hydroxy protecting group; Each of R₂, R₃, R₄ and R₅,independently, is hydrogen or an aliphatic group, or (R₂ and R₃) and/or(R₄ and R₅) collectively form a C₄₋₇Cycloalkyl; X is —CH₂—, —S—,—CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF₂—, —C═N(OR)— or —CH(F)—;wherein R is alkyl; G is —OH or —O^(⊖)M^(⊕), wherein M is a metal or anammonium moiety; R₁ is aryl or heteroaryl; X′ is halo; R′ is alkyl oraryl; and n is 0 to 3, provided that when n is 0, X is —CH₂—.
 2. Theprocess of claim 1, followed by additional Step F which comprisescontacting the compound of formula (VIII), wherein R₁ is heteroarylhaving an N heteroatom, with an oxidizing agent to form thecorresponding N-oxide derivative.
 3. The process of claim 1, followed bythe additional step of removing the hydroxyl-protecting group bycontacting compound (VIII) with a palladium catalyst to form thecompound of formula (IX)

wherein R₁, R₂, R₃, R₄, R₅, X and n are as defined above.
 4. The processof claim 1, wherein each of R₂, R₃ and R₅ is hydrogen; R₄ is butyl; X is—CH₂—; n is 1; Y is benzyl or t-butyldimethylsilyl; and R₁ is of theformula

wherein R₆ and R₉ are hydrogen; R₇ is hydrogen or C₁₋₇alkyl; and R₈ ishydrogen, halogen or C₁₋₇alkyl.
 5. The process of claim 2, wherein R₇ ishydrogen; and R₈ is fluoro.
 6. The process of claim 2, wherein R₇ isC₁₋₇ alkyl; and R₈ is hydrogen.
 7. The process of claim 1, wherein R₁ isof the formula (XIa)

wherein R₆, R₇ and R₉ are hydrogen; and R₈ is halogen or C₁₋₇alkyl. 8.The process of claim 7, wherein R₈ is fluoro.
 9. The process of claim 1,carried out at a temperature of about 0° C. to about 80° C., a pH ofabout 2 to about 12, and in one or more solvents selected from the groupconsisting of dioxane, methylene chloride, dichloromethane, toluene,acetone, methyl ethyl ketone, THF, isopropyl acetate, DMF and analcohol.
 10. A process comprising contacting a compound of the formula(I)

with a compound of the formula (II).Y—O—NH₂  (II) in the presence of a carboxy activating agent, in asuitable solvent under conditions suitable to form a compound of theformula (III)

wherein each of R₂, R₃, R₄ and R₅, independently, is hydrogen or alkyl,or (R₂ and R₃) and/or (R₄ and R₅) collectively form a C₄₋₇cycloalkyl;and Y is a hydroxy-protecting group.
 11. The process of claim 10,wherein R₂, R₃ and R₅ are hydrogen; R₄ is n-butyl; and Y is benzyl ort-butyldimethylsilyl.
 12. The process of claim 10 carried out at atemperature of about 5° C. to about 35° C. for about 2 hours to about 5hours, at a pH of about 3 to about 5, wherein the carboxy-activatingagent is DCC, CDMT or EDCl and the solvent is THF/water.
 13. A processcomprising contacting a compound of the formula (III)

with a compound of the formula (XIII).R′—SO₂—X′  (XIII) in the presence of a base in a suitable solvent, underconditions suitable to form a compound of the formula (IV)

wherein each of R₂, R₃, R₄ and R₅, independently, is hydrogen or alkyl,or (R₂ and R₃) and/or (R₄ and R₅) collectively form a C₄₋₇cycloalkyl; Yis a hydroxy-protecting group; X′ is halo; and R′ is alkyl or aryl. 14.The process of claim 13, wherein each of R₂, R₃ and R₅ are hydrogen; R₄is C₁₋₇alkyl; X′ is chloro; R′ is methyl or phenyl or toluyl; and Y isbenzyl or t-butyldimethylsilyl.
 15. The process of claim 10, wherein R₄is n-butyl; and R′ is methyl.
 16. The process of claim 10 carried out ata temperature of about −5° C. to about 5° C. for about 2 hours to about5 hours at a pH of about 9 to about 10, wherein the base is pyridine,DMAP, a trialkylamine, a resin-bound bases or a Hunig bases, and thesolvent is pyridine, THF or EtOAc.
 17. A process comprising contacting acompound of the formula (IV)

with a base in a suitable solvent under conditions suitable to form acompound of the formula (V)

wherein each of R₂, R₃, R₄ and R₅, independently, is hydrogen or alkyl,or (R₂ and R₃) and/or (R₄ and R₅) collectively form a C₄₋₇cycloalkyl;and Y is a hydroxy-protecting group.
 18. The process of claim 17,wherein each of R₂, R₃ and R₅ are hydrogen; R₄ is C₁₋₇alkyl; X′ ischloro; R′ is methyl or phenyl; and Y is benzyl or t-butyldimethylsilyl.19. The process of claim 17 wherein R₄ is n-butyl; and R′ is methyl. 20.The process of claim 17 carried out at a temperature of about 40° C. toabout 80° C. for about 2 hours to about 4 hours at a pH of about 8 toabout 12, wherein the base is potassium carbonate, lithium carbonate,sodium carbonate, lithium bicarbonate, sodium bicarbonate or an alkyllithium, and the solvent is acetone or methylethylketone.
 21. A processcomprising contacting a compound of the formula (V)

with a compound of the formula (VI)

in a suitable solvent optionally in the presence of an activator underconditions suitable t form a compound of the formula (VII)

wherein each of R₂, R₃, R₄ and R₅, independently, is hydrogen or alkyl,or (R₂ and R₃) and/or (R₄ and R₅) collectively form a C₄₋₇cycloalkyl; Yis a hydroxy-protecting group; X is —CH₂—, —S—, —CH(OH)—, —CH(OR)—,—CH(SH)—, —CH(SR)—, —CF₂—, —C═N(OR)— or —CH(F)—; wherein R is alkyl; R₁is aryl or heteroaryl; and n is 0 to 3, provided that when n is 0, X is—CH₂—.
 22. The process of claim 21, wherein each of R₂, R₃ and R₅ arehydrogen; R₄ is C₁₋₇alkyl; X is —CH₂—; Y is benzyl ort-butyldimethylsilyl; and R₁ is a moiety of the formula (XIa)

wherein R₆ and R₉ are hydrogen; R₇ is hydrogen or C₁₋₇alkyl; and R₈ ishydrogen, halogen or C₁₋₇alkyl.
 23. The process of claim 22, wherein R₄is n-butyl; and R₁ is a moiety of the formula

wherein R₇ is hydrogen; and R₈ is fluoro.
 24. The process of claim 21carried out at a temperature is of about 60° C. to about 80° C. forabout 5 hours to about 10 hours at a pH of about 5 to about 11, whereinthe activator is 2-ethylhexanoic acid, acetic acid or isobutryic acidand the solvent is THF, dioxane or dimethoxyethane.
 25. The process ofclaim 24 carried out in the absence of an activator and wherein thesolvent is MeOH.H₂O or EtOH.H₂O.
 26. A process comprising contacting acompound of the formula (VII)

with a formylating agent in a suitable solvent under conditions suitableto form a compound of the formula (VIII)

wherein each of R₂, R₃, R₄ and R₅, independently, is hydrogen or alkyl,or (R₂ and R₃) and/or (R₄ and R₅) collectively form a C₁₋₇cycloalkyl; Yis a hydroxy-protecting group; X is —CH₂—, —S—, —CH(OH)—, —CH(OR)—,—CH(SH)—, —CH(SR)—, —CF₂—, —C═N(OR)— or —CH(F)—; wherein R is alkyl; R₁is aryl or heteroaryl; and n is 0 to 3, provided that when n is 0, X is—CH₂—.
 27. The process of claim 26, wherein each of R₂, R₃ and R₅ arehydrogen; R₄ is C₁₋₇alkyl; X is —CH₂—; Y is benzyl ort-butyldimethylsilyl; and R₁ is a moiety of the formula (XIa)

wherein R₆ and R₉ are hydrogen; R₇ is hydrogen or C₁₋₇alkyl; and R₈ ishydrogen, halogen or C₁₋₇alkyl.
 28. The process of claim 26 wherein R₄is n-butyl; and R₁ is a moiety of the formula

wherein R₇ is hydrogen; and R₈ is fluoro.
 29. The process of claim 26carried out at a temperature of about 0° C. to about 25° C. for about 20minutes to about 1 hour, wherein the formylating agent is HCO₂H/Ac₂O ortrifluoroethylformate, and the solvent is EtOAc, isopropylacetate,t-butylacetate or THF.
 30. A compound of the formula (I)

wherein each of R₂, R₃, R₄- and R₅, independently, is hydrogen or alkyl,or (R₂ and R₃) collectively form a C₄₋₇cycloalkyl, provided that wheneither R₄ or R₅ is hydrogen, the other substituent, i.e., R₄ or R₅, isnot hydrogen or methyl.
 31. The compound of claim 30, wherein R₅ ishydrogen; and R₄ is C₂₋₇alkyl.
 32. The compound of claim 30 having theformula (Ib)

wherein G is —OH or —O^(⊖)M^(⊕), wherein M is a metal or an ammoniummoiety; and each of R₂, R₃ and R₅, independently, is hydrogen or alkyl,or (R₂ and R₃) collectively form a C₄₋₇cycloalkyl, provided that R₅ isnot n-butyl.
 33. The compound of claim 30 having the formula (Ia)


34. A compound selected from the group consisting of formulae (If)-(Ih)


35. A compound having the formula (VII)

wherein each of R₂, R₃. R₄ and R₅, independently, is hydrogen or alkyl,or (R₂ and R₃) can collectively form a C₄₋₇cycloalkyl; Y is ahydroxy-protecting group; X is —CH₂—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—,—CH(SR)—, —CF₂—, —C═N(OR)— or —CH(F)—; wherein R is alkyl; R₁ is aryl orheteroaryl; and n is 0 to 3, provided that when n is 0, X is —CH₂—, andthat R₄ and R₅ are different.
 36. The compound of claim 35, wherein eachof R₂, R₃ and R₅ are hydrogen; R₄ is C₁₋₇alkyl; X is —CH₂—; Y is benzylor t-butyldimethylsilyl; and R₁ is a moiety of the formula (XIa)

wherein R₆ and R₉ are hydrogen; R₇ is hydrogen or C₁₋₇alkyl; and R₈ ishydrogen, halogen or C₁₋₇alkyl.
 37. The compound of claim 36, wherein R₄is n-butyl; and R₁ is a moiety of the formula

wherein R₇ is hydrogen; and R₈ is fluoro.